This proposal focuses on three relatively rare vascular malformations that are poorly understood in terms of biological mechanisms, are resource-intensive to manage effectively and have high probability of serious neurological morbidity. Each disease is characterized by the development of a distinct category of vascular malformations and a unique spectrum of clinical and phenotypic outcomes, for which biological risk factors are either poorly understood or completely unknown. The identification of these risk factors would be of immediate significance for patient surveillance and for optimizing management. Further, although there is no specific medical therapies for these diseases, appropriate treatment (efficacy) trials will require risk stratification for selection and surrogate outcomes for trial development. The general effort is focused on the establishment of research grade, relational, scalable clinical databases to conduct observational or interventional trials. Further, we will identify novel markers for disease risk. These markers represent new approaches to diagnosis, prevention, and treatment of these three rare diseases and are appropriate for risk stratification, applicable to future clinical trials. The three projects synergize with one another in these common goals and objectives, in their use of common infrastructure elements, and in overlapping but complementary expertises of the investigators. Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu disease) is an autosomal dominant condition characterized by vascular malformations, specifically developing muco-cutaneous telangiectasia and solid organ AVMs (primarily brain, lung and liver). The systematic study of the epidemiology of BAVM lesions in HHT is difficult due to the rarity of BAVM lesions in HHT (i.e., pulmonary AVMs are much more common in HHT). Risk factors for spontaneous intracranial hemorrhage (ICH) are a major management consideration. However, while the clinical behavior of sporadic BAVM has been studied in depth, comparable studies for HHT are limited to small series of 20-30 cases. Here, we propose the first large-scale collaboration with 12 HHT Centers of Excellence in North America to perform a study of ICH in HHT patients harboring BAVM (Table 2). It is commonly assumed that HHT BAVMs are inherently less likely to rupture;we will critically examine this question and hypothesize that discrete angioarchitectural and genetic factors may signal high risk. In Aim 1, we will construct an HHT clinical research database. We expect a grand total of 875 HHT BAVM cases over the course of the project. Data will include demographics, symptomatology, cerebral angioarchitecture and basic data about other organ involvement. In Aim 2, we will determine risk factors for hemorrhage in HHT patients with BAVM. Although well known for sporadic AVMs, the risk factors for ICH in HHT BAVM are poorly characterized, and it is unknown whether the risk is similar to that of sporadic cases. This information is essential for rationale planning of potentially high risk interventional therapy (surgery, embolization, radiation). This aim will have both a cross-sectional analysis of ICH risk factors in HHT patients and a longitudinal component to compare ICH rate between HHT patients with BAVM to an already collected cohort of sporadic BAVM (n=900). Aim 3 will investigate the use of genotype as potential marker for increased ICH risk. This work is based on findings in sporadic BAVMs, in which polymorphic variation in several genes, mostly inflammatory, are associated with ICH, mostly in inflammatory genes. Although probably not causal, certain alleles are associated with increased risk of disease progression and/or ICH, and can therefore be useful as a biomarker in clinical management and risk stratification.